Cited by 231Cell death mechanisms and regulationAutophagy in Disease and TherapyCellular transport and secretion

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Active Ras Triggers Death in Glioblastoma Cells through Hyperstimulation of Macropinocytosis

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Overmeyer, Jean H., Kaul, Aparna, Johnson, Erin E., Maltese, William A.·2008·Molecular Cancer Research

DOI 10.1158/1541-7786.mcr-07-2036PMC PMC2994605

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Abstract

Expression of activated Ras in glioblastoma cells induces accumulation of large phase-lucent cytoplasmic vacuoles, followed by cell death. This was previously described as autophagic cell death. However, unlike autophagosomes, the Ras-induced vacuoles are not bounded by a double membrane and do not sequester organelles or cytoplasm. Moreover, they are not acidic and do not contain the autophagosomal membrane protein LC3-II. Here we show that the vacuoles are enlarged macropinosomes. They rapidly incorporate extracellular fluid-phase tracers but do not sequester transferrin or the endosomal protein EEA1. Ultimately, the cells expressing activated Ras detach from the substratum and rupture, coincident with the displacement of cytoplasm with huge macropinosome-derived vacuoles. These changes are accompanied by caspase activation, but the broad-spectrum caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone does not prevent cell death. Moreover, the majority of degenerating cells do not exhibit chromatin condensation typical of apoptosis. These observations provide evidence for a necrosis-like form of cell death initiated by dysregulation of macropinocytosis, which we have dubbed “methuosis.” An activated form of the Rac1 GTPase induces a similar form of cell death, suggesting that Ras acts through Rac-dependent signaling pathways to hyperstimulate macropinocytosis in glioblastoma. Further study of these signaling pathways may lead to the identification of other chemical and physiologic triggers for this unusual form of cell death. (Mol Cancer Res 2008;6(6):965–77)

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Authors: Overmeyer, J. H., Kaul, A., Johnson, E. E., & Maltese, W. A.
Affiliations: University of Toledo (US)
ORCID: Johnson, Erin E.
Maltese, William A.
Venue: Molecular Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2008-06-01
Volume: 6
Issue: 6
Pages: 965-977
ISSN: 1541-7786 (ISSN-L)
1557-3125
DOI: 10.1158/1541-7786.mcr-07-2036
PMC: PMC2994605
OpenAlex: W2018951108
Cited by: 229
References: 56
Citations by year: 2026: 10 · 2025: 30 · 2024: 22 · 2023: 15 · 2022: 14 · 2021: 16 · 2020: 12 · 2019: 9 · 2018: 14 · 2017: 12 · 2016: 16 · 2015: 12 · 2014: 14 · 2013: 10 · 2012: 7
FWCI: 2.06
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Molecular Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (R01 CA 34569, R01CA034569, R01CA115495)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords: activated Ras, glioblastoma, macropinocytosis, methuosis, necrosis-like cell death, macropinosomes, Rac1 GTPase, caspase activation, cytoplasmic vacuoles, cell detachment
MeSH terms: Brain Neoplasms, Glioblastoma, Humans, Necrosis, Pinocytosis, Vacuoles, Proto-Oncogene Proteins p21(ras), rac1 GTP-Binding Protein, Cell Line, Tumor

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Active Ras Triggers Death in Glioblastoma Cells through Hyperstimulation of Macropinocytosis

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